Category: Special Issues

Five-year follow-up analysis continues to show long-term survival in patients with PD-L1 <1% mNSCLC using OPDIVO®(nivolumab) + YERVOY®(ipilimumab) + 2 cycles of platinum-doublet chemo

RR

Expert opinion: Luis Raez, MD, FACP, FCCP, FASCO
Content sponsored by Bristol Myers Squibb

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) + 2 cycles of platinum-doublet chemotherapy in 1L mNSCLC

Checkmate 9LA, a randomized, open-label, phase 3 trial, led to the approval of OPDIVO + YERVOY + chemotherapy as a treatment for 1L r/m NSCLC with no EGFR or ALK genomic tumor aberrations and regardless of PD-L1 status.1,3‡ “In my practice, I see a large number of patients with PD-L1 <1% mNSCLC and, in general, PD-L1 <1% has a worse prognosis than PD-L1 >1%,” stated Dr Raez.

*In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm and 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in the comparator arm only); SQ: paclitaxel + carboplatin.1 †Dr Raez was compensated by BMS for his contributions to this article. ‡Although PD-L1 status was not a restriction on the trial’s eligibility criteria, it is not part of the approved indication.1

OPDIVO and YERVOY are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

Please see additional Important Safety Information for OPDIVO and YERVOY below, and U.S. Full Prescribing Information for OPDIVO and YERVOY.

The trial design of Checkmate 9LA included enrolling 719 eligible patients randomized 1:1 to receive either OPDIVO 360 mg q3w + YERVOY 1 mg/kg q6w + 2 cycles of platinum-doublet chemotherapy q3w (n=361) or platinum-doublet chemotherapy alone q3w (n=358).1 Key eligibility criteria included age of 18 years or older, stage IV or recurrent NSCLC, ECOG PS 0/1, and no prior systemic anticancer therapy.1 Treatment continued until disease progression, unacceptable toxicity, or for up to 2 years.1 Patients were stratified by histology (SQ vs NSQ), PD-L1 status (<1% vs ≥1%), and sex.4 The primary endpoint was OS and additional efficacy outcome measures were PFS, ORR, and DOR.3

Checkmate 9LA was the first phase 3 study to demonstrate improved OS regardless of PD-L1 expression.4 Furthermore, this is the only I-O combination with more than 1 in 5 patients with PD-L1 <1% alive at 5 years.1,3 A limitation to note is that Checkmate 9LA was not powered to detect differences in treatment effect in PD-L1 subgroups; therefore, results from this exploratory analysis should be interpreted with caution due to the limited patient numbers and potential imbalances in baseline characteristics within the subgroup.

In the primary analysis (minimum follow-up of 8.1 months), OPDIVO + YERVOY and chemotherapy demonstrated4:

  • Statistically significant and superior mOS (14.1 months; [95% CI: 13.2–16.2]) vs chemotherapy alone (10.7 months; [95% CI: 9.5–12.5]) in the ITT population (HR=0.69; [96.71% CI: 0.55–0.87]; P=0.0006)1
  • Improved overall survival5‡:
    • PD-L1 <1% patient population (14.0 months with OPDIVO + YERVOY and chemo [95% CI: 13.2–NR] vs 10.0 months with chemotherapy alone [95% CI: 7.7–13.7])
    • PD-L1 ≥1% patient population (14.2 months with OPDIVO + YERVOY and chemo [95% CI: 13.1–NR] vs 10.6 with chemotherapy alone [95% CI: 9.4–12.6])

‡Limitation: Checkmate 9LA was not powered to detect differences in treatment effect in PD-L1 subgroups; therefore, results from this exploratory analysis should be interpreted with caution due to the limited patient numbers and potential imbalances in baseline characteristics within the subgroup.

In a 5-year follow-up analysis, durable survival and continued response to treatment were observed with OPDIVO + YERVOY and 2 cycles of chemotherapy compared with chemotherapy alone. The following data were observed at the 57.3-month minimum follow-up3:

  • mOS3:
    • ITT patient population: 15.8 months (95% CI: 13.9–19.7) with OPDIVO + YERVOY and chemo vs 11.0 months (95% CI: 9.5–12.7) with chemo (HR=0.73; [95% CI: 0.62–0.85])
    • PD-L1 <1% patient population: 17.7 months (95% CI: 13.7–20.3) with OPDIVO + YERVOY and chemo vs 9.8 months (95% CI: 7.7–13.5) with chemo (HR=0.63; [95% CI: 0.49–0.83])
    • PD-L1 ≥1% patient population: 15.8 months (95% CI: 13.8–22.2) with OPDIVO + YERVOY and chemo vs 10.9 months (95% CI: 9.5–13.2) with chemo (HR=0.73; [95% CI: 0.59–0.90])

Durable overall survival rate in patients with PD-L1 <1%: The only I-O combination with more than 1 in 5 patients alive at 5 years1,3,5,6

Durable-OS-in-Patients-with-PD-L1-Less-Than-1%

Limitation: Checkmate 9LA was not powered to detect differences in treatment effect in PD-L1 subgroups; therefore, results from this exploratory analysis should be interpreted with caution due to the limited patient numbers and potential imbalances in baseline characteristics within the subgroup.

“22% is high compared with 8% and that is why we like the Checkmate 9LA regimen,” explained Dr Raez.

Overall survival in ITT population: Extended 5-year follow-up analysis1,3,6

OS-in-ITT-Population

  • mDOR3:
    • PD-L1 <1% patient population: 17.5 months with OPDIVO + YERVOY and chemo (95% CI: 6.9–37.8) vs 4.3 months with chemo (95% CI: 2.8–7.1)
    • PD-L1 ≥1% patient population: 11.8 months (95% CI: 8.6–20.3) vs 5.6 months and chemo (95% CI: 4.3–8.0)
    • ITT patient population: 12.4 months with OPDIVO + YERVOY and chemo (95% CI: 8.7–20.2) vs 5.6 months with chemo (95% CI: 4.4–7.1)

Duration of response in PD-L1 <1%: Extended 5-year follow-up analysis3

Duration-of-Response-in-PD-L1-Less-Than-1%

Limitation: Checkmate 9LA was not powered to detect differences in the treatment effect in this subgroup;
therefore, this exploratory analysis should be interpreted with caution because of the limited patient
numbers and potential imbalances in baseline characteristics within the subgroup.

“This regimen has markedly prolonged the duration of response at 5 years for 25% of patients with PD-L1 <1%” stated Dr. Raez.

Adverse reactions in >10% of patients receiving OPDIVO + YERVOY and 2 cycles of chemo1*†

Adverse-Reactions-Opdivo-Yervoy

  • OPDIVO + YERVOY with chemo was discontinued in 24% of patients due to adverse reactions, and 56% had at least one dose withheld for an adverse reaction1
  • Serious adverse reactions occurred in 57% of patients receiving OPDIVO + YERVOY with chemo1
  • The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia1
  • The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus1
  • Median number of doses was 9 for OPDIVO, 4 for YERVOY, and 2 cycles of chemo7
  • With a minimum follow-up of 57.3 months, no new safety signals were identified for OPDIVO + YERVOY and 2 cycles of chemo3*

Toxicity was graded per NCI CTCAE v4.1
*vs chemo. In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm and 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in the comparator arm only); SQ: paclitaxel + carboplatin.1 †Based on types of adverse reactions reported in 1L mNSCLC. Please note clinical trials are conducted under varying conditions, including different trial designs and dosing. Adverse reaction rates cannot be directly compared between trials.1 ‡Includes fatigue and asthenia.1 §Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, and synovitis.1 ║Includes colitis, ulcerative colitis, diarrhea, and enterocolitis.1 ¶Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain.1 #Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blennorrhagica, palmar-plantar erythrodysesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, and urticaria.1 **Includes pruritus and generalized pruritus.1 ††Includes cough, productive cough, and upper-airway cough syndrome.1 ‡‡Includes dyspnea, dyspnea at rest, and exertional dyspnea.1 §§Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine.1 ║║Includes dizziness, vertigo and positional vertigo.1

“The safety profile in the extended 5-year follow-up analysis of Checkmate 9LA was consistent with the previously known profiles for each component,” explained Dr Raez.

Dosing
OPDIVO® (nivolumab) + low-dose YERVOY® (ipilimumab) (1 mg/kg) and 2 cycles of chemo1

For the r/m NSCLC dosing regimen in combination with chemo: on the first week, 4 agents will be administered (OPDIVO 360 mg + YERVOY 1 mg/kg + platinum-doublet histology-based chemo†), followed by 3 agents (OPDIVO + platinum-doublet histology-based chemo†) on the third week, 2 agents (OPDIVO + YERVOY) on the sixth week, and OPDIVO monotherapy on the ninth week, followed by maintenance therapy of OPDIVO + YERVOY: OPDIVO 360 mg q3w + YERVOY 1 mg/kg q6w until disease progression, unacceptable toxicity, or for up to 2 years.1 Histology-based chemo: SQ patients: carboplatin AUC 6 + paclitaxel 200 mg/m2 q3w; NSQ patients: carboplatin AUC 5 or 6 or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 q3w. No chemo maintenance required.1

  • OPDIVO is administered as an IV infusion over 30 minutes1
  • YERVOY is administered as an IV infusion over 30 minutes2

Summary and conclusions
5-year follow-up analysis of Checkmate 9LA continues to show prolonged survival data with OPDIVO + YERVOY and chemo vs chemo alone in patients who have r/m NSCLC across PD-L1 <1% and ≥1% expression.1,3 “Checkmate 9LA shows patient survival data that may be impactful,” stated Dr. Raez.
1L=first line; ALK=anaplastic lymphoma kinase; AUC=area under the curve; CI=confidence interval; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EGFR=epidermal growth factor receptor; HR=hazard ratio; I-O=immuno-oncology; ITT=intent to treat; IV=intravenous; mDOR=median DOR; mNSCLC=metastatic NSCLC; mo=month; mOS=median OS; NR=not reached; NSCLC=non-small cell lung cancer; NSQ=non-squamous; ORR=overall response rate; OS=overall survival; PD-1=programmed death receptor-1; PD-L1=programmed death ligand 1; PFS=progression-free survival; Pt=platinum; q3w=every 3 weeks; q6w=every 6 weeks; r/m=recurrent or metastatic; SQ=squamous.

INDICATION
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

IMPORTANT SAFETY INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions

  • Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune- mediated adverse reactions.
  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
  • Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

  • OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-Mediated Colitis

  • OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-Mediated Hepatitis and Hepatotoxicity

  • OPDIVO and YERVOY can cause immune-mediated hepatitis.

Immune-Mediated Endocrinopathies

  • OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

Immune-Mediated Nephritis with Renal Dysfunction

  • OPDIVO and YERVOY can cause immune-mediated nephritis.

Immune-Mediated Dermatologic Adverse Reactions

  • OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
  • YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.
  • Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Other Immune-Mediated Adverse Reactions

  • The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.
  • In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.
  • Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

  • OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

  • Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

  • Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

  • In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

  • There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

  • In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Common Adverse Reactions

  • In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

References:

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  3. Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer. Published online August 25, 2024. doi:10.1016/j.ejca.2024.114296
  4. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211.
  5. Data on file. NIVO 566. Princeton, NJ: Bristol-Myers Squibb Company; 2020.
  6. Reck M, Ciuleanu T-E, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6(5):100273.
  7. Data on file. NIVO 562. Princeton NJ: Bristol-Myers Squibb Company; 2020.

© 2024 Bristol-Myers Squibb Company. OPDIVO® and YERVOY® are registered trademarks of Bristol-Myers Squibb Company.
7356-US-2400513 12/24

Defining durability with AUGTYRO® (repotrectinib), the next-generation TKI for ROS1+ NSCLC

RR

Expert opinion: Jyoti Malhotra, MD, MPH
Content sponsored by: Bristol Myers Squibb
Dr. Malhotra was compensated by BMS for her contributions to this article.

Introduction: Unmet need in ROS1+ NSCLC
The identification of ROS1 as a therapeutic target in NSCLC has led to the development and approval of several first-generation TKIs.3-5 Despite this, the median duration of response is ~2 years with these first-generation TKIs.6,7 A different approach is needed.

1L AUGTYRO in locally advanced or metastatic ROS1+ NSCLC
TRIDENT-1, a global, phase 1/2, single-arm, multicohort, open-label trial, led to the approval of AUGTYRO as a treatment option in adult patients for locally advanced or metastatic ROS1+ NSCLC.1,2,8 AUGTYRO is the first and only approved next-generation TKI for this indication.8,9 “This approval has made it possible for newly diagnosed patients to have access to [another] treatment option that may provide disease control,” stated Dr. Malhotra.

                                               TRIDENT-1 Trial Design1,3,10,11In TRIDENT-1, the phase 2 dose expansion cohort included 127 patients who were either TKI-naïve (n=71) or had received a TKI (n=56).2 The primary endpoint was ORR and some of the secondary efficacy outcome measures were DOR and intracranial response. Baseline characteristics were reported for patients who had and had not received a prior TKI.2

There are warnings and precautions associated with AUGTYRO to keep in mind. These include central nervous system adverse reactions, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatinine phosphokinase (CPK) elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.1 Additional information related to warnings and precautions can be found here.

In the primary analysis, efficacy results for the TKI-naïve population (n=71) treated with AUGTYRO were as follows12:

  • ORR of 79% ([95% CI: 68–88]; median follow-up for ORR data: 18.1 months)
    • CR of 6% (n=4)
    • PR of 73% (n=52)
  • mDOR of 34 months ([95% CI: 25.6–NE]; range: 1.4+ to 42.4+ months; median follow-up for DOR data: 24.0 months)1,10
  • icORR observed in 7/8 patients with measurable baseline brain metastasis (median follow-up for icORR data: 18.1 months)1,12

                         Change in tumor burden by BICR in the TKI-naïve population12*

                           *Three patients discontinued study treatment before completing any post-baseline scans.12

In a follow-up analysis, continued response to treatment was seen with AUGTYRO. At the 33.9-month median follow-up, efficacy results for the TKI-naïve population treated with AUGTYRO were as follows9:
• cORR of 79% (n=71; [95% CI: 68–88])
• mDOR of 34.1 months (n=71; [95% CI: 27.4–NE])
• icORR of 89% (n=9; [95% Cl: 52–100]) in patients with measurable baseline brain metastasis

“TRIDENT-1 demonstrated an ORR of 79%, but more notably, a long mDOR of 34 months—this is almost 3 years,” explained Dr. Malhotra.

In TRIDENT-1, the most common reactions reported in ≥20% of 426 patients treated with AUGTYRO at the recommended dose were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and cognitive impairment.1 AUGTYRO was discontinued in 7% of patients, interrupted in 50% of patients, and dosage was reduced in 38% of patients due to adverse reactions.1 Serious adverse reactions occurred in 35% of patients receiving AUGTYRO. The most frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, pleural effusion, and hypoxia. Fatal adverse reactions occurred in 3.5% of patients and included pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.1

AUGTYRO is a next-generation ROS1 TKI with a compact structure that is smaller than currently available ROS1 TKIs.1,13,14
• Potential to decrease the development of ROS1 resistance mutations
• Potential to circumvent known ROS1 resistance mutations
• Physiochemical parameters for enhanced intracranial activity

                                    Mechanism of Action1,13


Dosing of AUGTYRO
The recommended oral dose of AUGTYRO is1:
• 160 mg (4x 40-mg capsules, or a single 160-mg capsule, QD) for the first 14 days
• 160 mg (4x 40-mg capsules, or a single 160-mg capsule, BID) on Day 15 and onward, until disease progression or unacceptable toxicity

“More recently, the 160 mg tablet is also available for use, which is great because now patients only need to take one tablet,” stated Dr. Malhotra. AUGTYRO can be taken with or without food.1 Patients should be advised not to drink grapefruit juice or eat grapefruit while taking AUGTYRO.1 Capsules should be swallowed whole at approximately the same time every day as prescribed.1 Contents of the capsule should not be opened, crushed, chewed, or dissolved.1 If a dose is missed or if a patient vomits at any time after taking a dose, instruct patients to skip the dose and resume at a regularly scheduled time.1 Two doses should not be taken at the same time.1 Adjustable dosing allows for dose modification if needed for adverse reactions. Recommended dosage reductions for adverse reactions are the following1:

  • For the dose of 160 mg QD:
    • First dose reduction: 120 mg QD
    • Second dose reduction: 80 mg QD
  • For the dose of 160 mg BID:
    • First dose reduction: 120 mg BID
    • Second dose reduction: 80 mg BID

A prescription for 40-mg capsules is required for dose reductions.1 Additional detailed dose reduction recommendations are available for key adverse reactions.1

Summary and conclusions
AUGTYRO is the next-generation TKI helping patients with ROS1+ NSCLC start strong.1,2,9 Results from the TRIDENT-1 trial and continued response for TKI-naïve patients at the ~3-year follow-up analysis support its current place in therapy.1,2,9 “AUGTYRO is definitely my preferred drug for 1L ROS1+ NSCLC treatment—we are seeing responses for years,” stated Dr. Malhotra.

1L=first line; ATP=adenosine triphosphate; BICR=blinded independent central review; BID=twice daily; CI=confidence interval; CNS=central nervous system; cORR=confirmed ORR; CR=complete response; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group performance status; EXP=expansion cohort; icORR=intracranial ORR; mDOR=median DOR; mNSCLC=metastatic NSCLC; NE=not evaluable; NSCLC=non-small cell lung cancer; ORR=overall response rate; PFS=progression-free survival; PR=partial response; QD=everyday; QTc=corrected QT; RECIST=Response Evaluation Criteria in Solid Tumors; ROS1=ROS proto oncogene 1; RP2D=recommended phase 2 dose; TKI=tyrosine kinase inhibitor.

INDICATION
AUGTYRO® (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

IMPORTANT SAFETY INFORMATION
Warnings & Precautions
Central Nervous System Adverse Reactions
• Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.
• Dizziness, including vertigo, occurred in 65%; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 11% required dose reduction of AUGTYRO due to dizziness.
• Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 5% of patients, 8% required dose reduction and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia.
• Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction and 0.5% permanently discontinued AUGTYRO due to cognitive adverse reactions.
• Mood disorders occurred in 6% of patients. Mood disorders occurring in >1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% required a dose reduction due to mood disorders.
• Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in >1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% required a dose reduction due to sleep disorders.
• The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.
• Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Interstitial Lung Disease (ILD)/Pneumonitis
• Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
• Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed.
Hepatotoxicity
• Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%.
• Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.
Myalgia with Creatine Phosphokinase (CPK) Elevation
• AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.
• Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement.
Hyperuricemia
• Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
• Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Skeletal Fractures
• Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients.
• Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients less than 12 years of age.
• Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.
Embryo-Fetal Toxicity
• Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose.
Adverse Reactions
• The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Drug Interactions
Effects of Other Drugs on AUGTYRO
Strong and Moderate CYP3A Inhibitors
• Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.

P-gp Inhibitors
• Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO.
Strong and Moderate CYP3A Inducers
• Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.
Effects of AUGTYRO on other Drugs
Certain CYP3A4 Substrates
• Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
• Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.
Contraceptives
• Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
• Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females of childbearing potential to use an effective nonhormonal contraceptive.
Please see US Full Prescribing Information for AUGTYRO.

References:
1. AUGTYRO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
2. Drilon A, Camidge DR, Lin JJ, et al. Repotrectinib in ROS1 fusion–positive non–small-cell lung cancer. N Engl J Med. 2024;390(2):118-131.
3. Lin JJ, Shaw AT. Recent advances in targeting ROS1 in lung cancer. J Thorac Oncol. 2017;12(11):1611-1625.
4. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-1203.
5. US Food and Drug Administration. FDA Approves Crizotinib Capsules. Published March 11, 2016. Accessed October 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-capsules.
6. Drilon A, Chiu CH, Fan Y, et al. Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC. JTO Clin Res Rep. 2022;3(6):100332. Published 2022 Apr 29. doi:10.1016/j.jtocrr.2022.100332.
7. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30(7):1121-1126. doi:10.1093/annonc/mdz131.
8. US Food and Drug Administration. Center for Drug Evaluation and Research. AUGTYRO Label and Approval History. NDA218213. Published November 15, 2023. Accessed October 16, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/218213Orig1s000ltr.pdf.
9. Drilon A, Dziadziuszko R, Camidge DR, et al. Repotrectinib in tyrosine kinase inhibitor (TKI)-naïve patients with advanced ROS1 fusion-positive (ROS1+) NSCLC in the phase 1/2 TRIDENT-1 trial: clinical update, treatment beyond progression and subsequent therapies. Oral presentation at ASCO 2024. Poster 386.
10. Cho BC, Camidge DR, Lin JJ, et al. Repotrectinib in patients with ROS1 fusion-positive non-small cell lung cancer: update from the pivotal phase 1/2 TRIDENT-1 trial. Oral presentation at WCLC 2023. Abstract OA03.06.
11. ClinicalTrials.gov. A study of repotrectinib (TPX-0005) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. Accessed April 19, 2024. https://clinicaltrials.gov/study/NCT03093116.
12. Cho BC, Lin JJ, Camidge DR, et al. Pivotal topline data from the phase 1/2 TRIDENT-1 trial of repotrectinib in patients with ROS1+ advanced non-small cell lung cancer (NSCLC). Oral presentation at ENA 2022. Abstract 2LBA.
13. Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent-front mutations. Cancer Discov. 2018;8(10):1227-1236.
14. Murray BW, Rogers E, Zhai D, et al. Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Mol Cancer Ther. 2021;20(12):2446-2456. doi:10.1158/1535-7163.MCT-21-0632

© 2024 Bristol-Myers Squibb Company. AUGTYRO®, is a registered trademark of
Bristol-Myers Squibb Company.
3600-US-2400322 11/24

What is the Real-World Evidence for the Effectiveness of Mogamulizumab in Patients with Mycosis Fungoides and Sézary Syndrome?

RR

Written by: Francine Foss, MD
Professor of Medicine (Hematology) and Dermatology
Director, Multidisciplinary T cell Lymphoma Program, Hematology; Scientific Leader, Lymphoma CRT
Yale Cancer Center
Content sponsored by Kyowa Kirin, Inc.
Dr. Foss is a paid consultant for Kyowa Kirin and was compensated for her contribution in drafting this article.

POTELIGEO® (mogamulizumab–kpkc), indicated for the treatment of adult patients with relapsed or refractory Mycosis Fungoides (MF) or Sézary Syndrome (SS) after at least one prior systemic therapy, is a first-in-class humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4), a protein consistently expressed on cancerous cells seen in both MF and SS.1-3

POTELIGEO received FDA approval based on results of the MAVORIC trial, a randomized, open-label, phase 3 trial that compared its efficacy with that of an active comparator, vorinostat, in previously treated patients with relapsed or refractory MF or SS. In MAVORIC, patients receiving mogamulizumab (n=186) demonstrated efficacy superior to those receiving vorinostat (n=186) in the prespecified primary endpoint, with significantly longer progression-free survival (PFS) (7.6 vs 3.1 months; hazard ratio: 0.53, 95% CI [0.41, 0.69], P<0.001). For the secondary endpoint, overall response rate (ORR), significantly more patients achieved a response to mogamulizumab vs the comparator (28% vs 5%, P<0.001). When evaluated by disease compartment, response rates were higher with mogamulizumab compared with vorinostat in the blood (67% vs 18%), skin (42% vs 16%), and lymph nodes (15% vs 4%). The most common adverse reactions (reported in ≥20% of patients) were rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection.4

The OMEGA study was a retrospective analysis of real-world patients receiving mogamulizumab in 14 centers throughout France. The full study-report article can be accessed at https://doi.org/10.1111/jdv.19134. A total of 122 patients were reviewed, 53 with MF and 69 with SS. All had been treated with mogamulizumab from February 2014 until March 2020.5 The OMEGA study contains information that is not included in the FDA-approved labeling for POTELIGEO; the study included 2 patients with SS in whom mogamulizumab was administered as a first-line therapy. OMEGA also reported a serious adverse reaction, vitiligo (3 patients [2.4%]), that was not captured in the MAVORIC trial. It is not known if there were variations from the FDA-approved labeling in the dosing schedule for any patients included in the study. Also, OMEGA differed from MAVORIC by defining treatment responses as complete or partial response (CR or PR) that occurred at any time, and for no prespecified duration post-initiation of mogamulizumab. In MAVORIC, by definition, treatment responses were required to be confirmed CR or PR at 2 or more consecutive assessments spaced at least 8 weeks apart.5

In the OMEGA study, key outcome measures were:
Primary endpoint: Best overall response rate (bORR)a
Secondary endpoints: bORR by compartment (skin, blood, lymph nodes, viscera)b and safety
Exploratory endpoint: PFS

a Percentage of patients achieving a global overall response (CR or PR) at any time and for no prespecified duration.
b Percentage of patients achieving a CR or PR in the specified compartment at any time and for no prespecified duration.

As shown in Figure 1, in the entire patient population, bORR was 58.7% (12.8% CR; 45.9% PR). In patients with SS, bORR was 69.5% (16.9% CR; 52.5% PR), and in patients with MF, bORR was 46.0% (8.0% CR; 38.0% PR). The median time to response under treatment (CR or PR) was similar according to disease subtype (3.1 months for patients with SS and MF; respective ranges: 01–25.0, and 0.3–44.3 months).5

Best-ORR-Primary-Endpoint

Responses were seen across all involved disease compartments, as seen in Table 1.5

Best-Responses-Blood-Skin-LN-Viscera-Secondary-Endpoint

As seen in Figure 2, in the overall analysis population (n=122), the median PFS was estimated at 15.0 months (95% CI [9.0–50.8]). It was longer in patients with SS than in patients with MF (20.3 months [11.7–not reached] vs. 8.8 months [4.6–43.0]) but no significant difference between disease subtypes was shown (P= 0.0542).5

Progression-Free-Survival

The percentage of patients who experienced a serious adverse reaction (AR) was consistent with MAVORIC (18.5% vs 20% in MAVORIC).1,2 Discontinuations of mogamulizumab due to ARs occurred in 15 patients (12.1%) rash was the most common reason for permanent discontinuation (9 patients; 7.3%). One patient discontinued due to thrombopenia and one patient discontinued due to an infusion-related reaction (0.8% each).5 The most common ARs can be seen in Table 2.

Adverse-Drug-Reactions

Limitations of the OMEGA study include its non-interventional and retrospective design, a patient population less selective than those in clinical trials, and overlap of 20 patients that were also part of the MAVORIC trial. The results are in line with efficacy and safety data demonstrated in the global clinical trial MAVORIC, and supports the effectiveness of mogamulizumab in real-world clinical practices.

INDICATION
POTELIGEO injection for intravenous infusion is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.

IMPORTANT SAFETY INFORMATION
Warnings and Precautions
• Dermatologic toxicity: Monitor patients for rash throughout the course of treatment. For patients who experienced dermatologic toxicity in Trial 1, the median time to onset was 15 weeks, with 25% of cases occurring after 31 weeks. Interrupt POTELIGEO for moderate or severe rash (Grades 2 or 3). Permanently discontinue POTELIGEO for life-threatening (Grade 4) rash or for any Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).
• Infusion reactions: Most infusion reactions occur during or shortly after the first infusion. Infusion reactions can also occur with subsequent infusions. Monitor patients closely for signs and symptoms of infusion reactions and interrupt the infusion for any grade reaction and treat promptly. Permanently discontinue POTELIGEO for any life-threatening (Grade 4) infusion reaction.
• Infections: Monitor patients for signs and symptoms of infection and treat promptly.
• Autoimmune complications: Interrupt or permanently discontinue POTELIGEO as appropriate for suspected immune-mediated adverse reactions. Consider the benefit/risk of POTELIGEO in patients with a history of autoimmune disease.
• Complications of allogeneic HSCT after POTELIGEO: Increased risks of transplant complications have been reported in patients who received allogeneic HSCT after POTELIGEO. Follow patients closely for early evidence of transplant-related complications

Adverse Reactions
• The most common adverse reactions (reported in ≥10% of patients) with POTELIGEO in the clinical trial were rash, including drug eruption (35%), infusion reaction (33%), fatigue (31%), diarrhea (28%), drug eruption (24%), upper respiratory tract infection (22%), musculoskeletal pain (22%), skin infection (19%), pyrexia (17%), edema (16%), nausea (16%), headache (14%), thrombocytopenia (14%), constipation (13%), anemia (12%), mucositis (12%), cough (11%), and hypertension (10%).

Please see the full Prescribing Information for POTELIGEO at www.poteligeohcp.com for additional information.

You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References:
1. Ferenczi K, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol. 2002;119(6):1405-1410.
2. Yoshie O, et al. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood. 2002;99(5):1505-1511.
3. Ishida T, et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003;9(10 Pt 1):3625-3634.
4. POTELIGEO [package insert]. Kyowa Kirin Inc., Princeton, NJ USA.
5. Beylot-Barry M, Quereux G, Nardin C, et al. Effectiveness of mogamulizumab in patients with mycosis fungoides or Sézary syndrome: a multicentre, retrospective, real-world French study. J Eur Acad Dermatol Venereol. 2023;37(9):1777-1784.

POTELIGEO is a registered trademark of Kyowa Kirin Co., Ltd.
© 2024 Kyowa Kirin, Inc. All rights reserved.
510 Carnegie Center Dr. Princeton, NJ 08540 USA

COMM-US-POT-0274 May 2024

Durable survival with OPDIVO ® (nivolumab) + chemotherapy (fluoropyrimidine- and platinum-based) vs chemotherapy alone, a first-line treatment of metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, regardless of PD-L1 status at 4 years of follow-up1,2

RR

Ronan Kelly, MD, MBA,
The Charles A. Sammons Cancer Center,
Baylor University Medical Center, Dallas, Texas*
Content sponsored by: Bristol Myers Squibb
*Dr Kelly was compensated by BMS for his contribution in drafting this article.

Introduction: Overview of gastroesophageal adenocarcinoma
Gastroesophageal adenocarcinomas consist of a heterogeneous group of tumors, including gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma (EAC), all of which are aggressive malignancies with poor outcomes.3-6 The aggressive natures of GC and EAC may contribute to their respective statuses as two of the most common causes of cancer-related death globally.7

Gastroesophageal-CancersCheckmate 649 led to the approval of nivolumab (OPDIVO) + chemotherapy as the first chemoimmunotherapy combination for all eligible patients with HER2-negative† GC/GEJC/EAC regardless of PD-L1 status.1,8,9 Prior to this approval, chemotherapy was the only available 1L treatment option for metastatic GC/GEJC/EAC.10 Furthermore, to date, Checkmate 649 has the longest follow-up survival data in GC vs chemotherapy for any I-O–based regimen with a minimum follow-up of 48.1 months (median of 59.3 months), and showed durable survival data with OPDIVO + chemotherapy in GC/GEJC/EAC.1,2,11 OPDIVO can be given q2w or q3w, which synchronizes with the q2w FOLFOX and q3w CapeOx dosing schedules.1 “The flexible dosing schedule of OPDIVO has made it more convenient to integrate into my clinical practice,” stated Dr. Kelly.

†Indication has no restriction on HER2 status; trial included HER2-negative patients and patients with unknown HER2 status, while excluding those with known HER2-positive status.1

OPDIVO + chemotherapy in 1L metastatic GC/GEJC/EAC
With the longest follow-up survival data in GC vs chemotherapy for any I-O–based regimen and durable survival data in GC/GEJC/EAC, OPDIVO + fluoropyrimidine- and platinum-containing chemotherapy is currently FDA-approved in 1L metastatic non–HER2-positive† GC/GEJC/EAC, regardless of PD-L1 status (no testing required).1,2,9 The approval of this combination was based on the results of Checkmate 649, a global phase 3 study in patients with 1L metastatic GC/GEJC/EAC.1,8 Key exclusion criteria included known HER2-positive status and untreated CNS metastases.8 The study recruited all eligible patients regardless of PD-L1 expression.1,8

Trial-DesignCheckmate 649 enrolled 1581 patients randomized 1:1 to receive either OPDIVO + chemotherapy (n=789) or chemotherapy alone (n=792). The dual primary endpoints were OS and PFS in PD-L1 CPS ≥5. OS in PD-L1 CPS ≥1 and in all-comers were secondary endpoints, but were powered to measure statistical significance through hierarchical analysis. Baseline characteristics were consistent among all randomized patients and patients with PD-L1 CPS ≥5. Checkmate 649 was the first phase 3 trial to achieve positive results in the evaluation of a PD-1 inhibitor in combination with FOLFOX or CapeOx, allowing for synchronized I-O dosing options with the preferred chemotherapy.8

There are warnings and precautions associated with OPDIVO to keep in mind. These include severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.1 Additional information related to warnings and precautions can be found here .

Overall-Survival-in-all-randomized-patientsIn the primary analysis (minimum follow-up of 12.1 months), OPDIVO + chemotherapy demonstrated superior OS in all randomized patients and patients with PD-L1 CPS ≥5, as compared to chemotherapy alone. In all randomized patients, mOS was 13.8 mos with OPDIVO + chemotherapy vs 11.6 mos with chemotherapy (HR=0.80; 95% CI: 0.71–0.90; P=0.0002). In patients with PD-L1 CPS ≥5 (n=955), mOS was 14.4 mos with OPDIVO + chemotherapy vs 11.1 mos with chemotherapy (HR=0.71; 95% CI: 0.61–0.83; P<0.0001).1 The 12-month OS rate in all randomized patients was 55% with OPDIVO + chemotherapy vs 48% with chemotherapy.8 “In my opinion, clinical trial data with OPDIVO + chemotherapy was a landmark. For the first time in a non–HER2-positive population, patients were able to break through the 1-year mOS barrier,” explained Dr. Kelly.

Durable survival data was observed for this OPDIVO-based regimen vs chemotherapy alone in GC/GEJC/EAC. The follow-up analysis at 48.1 months reported a mOS of 13.7 mos (95% CI: 12.4–14.5) with OPDIVO + chemotherapy vs 11.6 mos (95% CI: 10.9–12.5) with chemotherapy in all randomized patients (HR=0.79; 95% CI: 0.71–0.88), and 14.4 mos (95% CI: 13.1–16.2) with OPDIVO + chemotherapy vs 11.1 mos (95% CI: 10.1–12.1) with chemotherapy in patients with PD-L1 CPS ≥5 (HR=0.70; 95% CI: 0.61–0.81). The 48-month OS rate was 13% vs 8% for OPDIVO + chemotherapy vs chemotherapy, respectively, in all randomized patients.2

In Checkmate 649, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain. OPDIVO and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction. Serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.1

An additional characteristic of OPDIVO is its flexible dosing schedule. Based on both the FDA-approved label and Checkmate 649 trial design, OPDIVO offers flexible synchronized dosing options based on chemotherapy preference, and “in my experience, allows scheduling according to the patient and clinician preference,” stated Dr. Kelly. Checkmate 649 evaluated OPDIVO (q2w or q3w) in combination with physician’s choice of either FOLFOX given q2w or CapeOx given q3w in the first-line treatment of certain metastatic gastroesophageal cancers. Treatment can be continued until disease progression, unacceptable toxicity, or up to 2 years.1

Synchronized-dosing-options-for-checkmate-649
Summary and conclusions
With the longest follow-up survival data in GC vs chemotherapy for any I-O–based regimen and durable survival data in GC/GEJC/EAC, OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy is an approved 1L treatment option for all eligible patients with non–HER2-positive† GC/GEJC/EAC, regardless of PD-L1 status.1,2 OPDIVO also offers synchronized dosing options to align with preferred chemotherapies, including both FOLFOX and CapeOx, which can be used every 2 or 3 weeks, respectively.1 “I believe Checkmate 649 may act as a new benchmark moving forward and novel therapeutics may be compared against it,” stated Dr. Kelly.

1L=first line; CapeOx=capecitabine and oxaliplatin; CI=confidence interval; CNS=central nervous system; CPS=combined positive score; FOLFOX=leucovorin, fluorouracil, and oxaliplatin; GEJ=gastroesophageal junction; HER2=human epidermal growth factor receptor 2; HR=hazard ratio; I-O=immuno-oncology; IV=intravenous; mo=month; mOS=median OS; mPFS=median PFS; ORR=overall response rate; OS=overall survival; PD-1=programmed death receptor-1; PD-L1=programmed death ligand 1; PFS=progression-free survival; q2w=every 2 weeks; q3w=every 3 weeks; ROW=rest of world.

INDICATION
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
OPDIVO (10 mg/mL) is an injection for intravenous use.

IMPORTANT SAFETY INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
• Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.
• Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
• Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
• OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).
Immune-Mediated Colitis
• OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).
Immune-Mediated Hepatitis and Hepatotoxicity
• OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).
Immune-Mediated Endocrinopathies
• OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
• In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).
• In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).
• In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).
• In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).
• In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).
• In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.
Immune-Mediated Nephritis with Renal Dysfunction
• OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).
Immune-Mediated Dermatologic Adverse Reactions
• OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
• Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
• In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).
Other Immune-Mediated Adverse Reactions
• The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.
• Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
Infusion-Related Reactions
• OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
• Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.
• Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
• Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.
Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
• In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Lactation
• There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.
Serious Adverse Reactions
• In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.
Common Adverse Reactions
• In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see US Full Prescribing Information for OPDIVO.

References:
1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
2. Shitara K, Moehler M, Ajani JA, et al. Nivolumab plus chemotherapy vs chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: 4-year follow-up of the CheckMate 649 study. Oral presentation at ASCO GI 2024. Abstract 306.
3. Mantziari S, St Amour P, Abboretti F, et al. A comprehensive review of prognostic factors in patients with gastric adenocarcinoma. Cancers (Basel). 2023;15(5):1628.
4. Imamura Y, Watanabe M, Oki E, Morita M, Baba H. Esophagogastric junction adenocarcinoma shares characteristics with gastric adenocarcinoma: literature review and retrospective multicenter cohort study. Ann Gastroenterol Surg. 2020;5(1):46-59.
5. Rogers MP, DeSantis AJ, DuCoin CG. Oligometastatic adenocarcinoma of the esophagus: current understanding, diagnosis, and therapeutic strategies. Cancers (Basel). 2021;13(17):4352.
6. Paydary K, Reizine N, Catenacci DVT. Immune-checkpoint inhibition in the treatment of gastro-esophageal cancer: a closer look at the emerging evidence. Cancers (Basel). 2021;13(23):5929.
7. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.
8. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40.
9. Janjigian YY, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab vs chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: CheckMate 649 study. Oral presentation at ESMO 2021. Abstract LBA7.
10. Shankaran V, Xiao H, Bertwistle D, et al. A comparison of real-world treatment patterns and clinical outcomes in patients receiving first-line therapy for unresectable advanced gastric or gastroesophageal junction cancer versus esophageal adenocarcinomas. Adv Ther. 2021;38:
707-720.
11. BMS-REF-NIVO-0256. Princeton, NJ: Bristol-Myers Squibb Company; 2024.

© 2024 Bristol-Myers Squibb Company. OPDIVO® is a registered trademark of Bristol-Myers Squibb Company.
1506-US-2300555 01/24

Targeting ESR1 Mutations in Estrogen-Positive Advanced Breast Cancer

RR

Written By: Debra Patt, MD, PhD, MBA

In the golden age of oncology, many patients can now live with cancer as a chronic disease. Understanding how to optimally block cancer growth and how cancers develop mechanisms of resistance is critical to improving therapy.

For most patients with advanced breast cancer, estrogen blockade is the mainstay of early cancer treatments. Optimizing estrogen blockade in combination with other targets has dramatically improved progression-free and overall survival in patients with advanced breast cancer. Optimizing endocrine blockade in patients with ER+ advanced breast cancer is not only an effective therapy that improves outcomes, but also delays other systemic therapy, like chemotherapy, which have a toxicity profile that is typically more severe than endocrine therapy alone. By delaying chemotherapy with effective endocrine therapy, patients can enjoy longer disease-free intervals and maintain a high quality of life. While estrogen-positive breast cancer can be targeted by many estrogen-targeted therapies, resistance to aromatase inhibition through the development of ESR1 mutations is an important mechanism of resistance that contributes to cancer progression via the endocrine blockade.1

As we continue to make progress in cancer care, becoming familiar with new therapies is critical. This article will review elacestrant, approved by the Food and Drug Administration (FDA) in January 2023 for patients with estrogen receptor-positive (ER+) advanced breast cancer with ESR1 mutations after at least one line of endocrine therapy.

The superior response among patients with ESR1 mutations led to FDA approval among patients with ESR1 mutations who had received at least one line of endocrine therapy. Because ESR1 mutation status is central to FDA approval and the basis of many coverage determinations from payers, assessing ESR1 mutation status accurately is an important aspect of treatment. ESR1 mutations can develop in patients with ER+ advanced breast cancer and can change over time. In patients with treatment naïve early-stage breast cancer, de novo ESR1 mutations are relatively rare, but as patients are exposed to therapy, ESR1 mutations are acquired, making them a common mechanism of resistance in patients with metastatic disease.2 Because mutations develop over time with the evolutionary pressure of therapy, a patient’s ESR1 mutation status, when they are initially diagnosed with ER+ metastatic disease, can later change after exposure to aromatase inhibition. If analysis for ESR1 mutations is conducted early in a patient’s treatment and is found negative, resistance may emerge and only be demonstrated with subsequent molecular testing. There is evidence that blood-based serial testing may be a useful way to identify patients who are eligible for treatment.3 In January 2023, Guardant Health, through the Guardant 360 CDx, was approved by the FDA as a tool to test the blood for ESR1 mutations to assess for eligibility for elacestrant. By using sequential serologic testing, patients can have an assessment of molecular characteristics without undergoing additional biopsy. Because such a small number of patients have ESR1 mutations when they are treatment naïve, but it becomes much more likely through the course of a patient’s disease, repeat testing is the primary way to assess if ESR1 mutations have evolved over time, and can be conducted via plasma assessment.

Elacestrant works by binding estrogen receptor alpha and acting as a Selective Estrogen Receptor Down regulator (SERD), allowing degradation of the estrogen receptor. The FDA approved elacestrant in 2023 based on the reporting of the phase III EMERALD trial showing that patients with ER-positive and HER2 negative advanced breast cancer who had had one to two lines of endocrine therapy, pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and not more than one line of chemotherapy, achieved a significant progression-free survival advantage when treated with elacestrant in comparison to other therapy.4 The population was further stratified as the whole population vs. just those with ESR1 mutations. In the entire population treated with elacestrant, PFS was prolonged (HR=0.70; 95% CI=0.55-0.88), and the results were more striking in those with ESR1 mutations (HR=0.55; 95% CI=0.39-0.77). In this group of pretreated patients with advanced breast cancer, ESR1 mutations were detected in 47.8% of patients. The progression-free survival of patients in the EMERALD trial was 3.8 months among patients receiving elacestrant in comparison to 1.9 months for other commonly prescribed endocrine therapies.

Elecestrant was well tolerated with treatment-related grade 3/4 adverse events in 7.2% of patients receiving elecestrant in comparison to 3.1% in patients receiving standard-of-care. Nausea was the most common side effect occurring to any extent in 35% of patients receiving elecestrant (though grade 3 was 2.5% and grade 4 was 0.9%) in comparison to 18.8% in patients who were receiving standard-of-care treatment. Other common side effects include abdominal pain, vomiting, diarrhea, constipation, elevation of liver function tests, cytopenias, hyponatremia, and fatigue. To mitigate side effects, it can help to take the medication with food, administer it at the same time each day, and use supportive anti-nausea and anti-diarrheal guidance upfront, in addition to dose reductions as appropriate.

In our modern era of cancer treatment, optimizing the use of incremental therapy can benefit patients. Making sure we consider ESR1 mutations in patients with ER+ advanced breast cancer, offer appropriate testing as patients are exposed to different treatments, and anticipate and mitigate side effects as appropriate will help us manage patients with ER+ advanced breast cancer optimally.

References
1) Brett, J.O., Spring, L.M., Bardia, A. et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 23, 85 (2021). https://doi.org/10.1186/s13058-021-01462-3.
2) Kinslow CJ, Tang A, Chaudhary KR, Cheng SK. Prevalence of Estrogen Receptor Alpha (ESR1) Somatic Mutations in Breast Cancer. JNCI Cancer Spectr. 2022 Sep 1;6(5):pkac060. doi: 10.1093/jncics/pkac060. PMID: 35959983; PMCID: PMC9438742.
3) Sundaresan TK, Dubash TD, Zheng Z, Bardia A, Wittner BS, Aceto N, Silva EJ, Fox DB, Liebers M, Kapur R, Iafrate J, Toner M, Maheswaran S, Haber DA. Evaluation of endocrine resistance using ESR1 genotyping of circulating tumor cells and plasma DNA. Breast Cancer Res Treat. 2021 Jul;188(1):43-52. doi: 10.1007/s10549-021-06270-z. Epub 2021 Jun 8. PMID: 34101078; PMCID: PMC8667563.
4) Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. doi: 10.1200/JCO.22.00338. Epub 2022 May 18. Erratum in: J Clin Oncol. 2023 Aug 10;41(23):3962. PMID: 35584336; PMCID: PMC9553388.

Clinical Pearls on Abemaciclib

RR

Written by: Debra Patt, MD, PhD, MBA

In our lifetime, the CDK 4/6 inhibitors have improved the quality of life and progression-free survival for patients with estrogen receptor (ER)-positive/human epidermal growth factor 2- (HER2)-negative breast cancer more than any other drug. Giving patients the opportunity for treatment allows them to realize the dream of modern cancer therapy. Over time, these drugs continue to show great promise in the metastatic setting and in high-risk adjuvant breast cancer patients. Understanding their optimal use and managing their toxicity will get us closer to supporting our patients to live well without cancer. This article will address abemaciclib in metastatic breast cancer and also its use in early-stage breast cancer, including the update of FDA guidance and also data including 4-year follow up.

Abemaciclib in Metastatic Breast Cancer

The first CDK4/6 inhibitor palbociclib, was approved by the FDA in 2016, followed by ribociclib and abemaciclib which were approved the following year. These drugs as a class have made a palpable difference in the lives of breast cancer patients. They have not only improved progression-free and overall survival but have also allowed patients with advanced cancer to live with the disease without the burden of highly toxic intravenous chemotherapy. In that way, many patients control their cancer just like hypertension or other chronic illnesses, with pills that have minimal impact on their quality of life.

The three CDK4/6 inhibitors are often discussed comparatively, but we do not yet have direct comparative data, limiting decisions on therapy to our understanding of each of them individually and their efficacy and toxicity profiles.

Some differences of importance across the drugs in the metastatic setting are efficacy and toxicity. See Table 1 for the designs of the metastatic trials and their efficacy in comparison to the control arms. In addition, there are important differences in adverse effect profiles, seen in Table 2. It is notable that in the frontline trials, many patients were managed with dose reduction. This is an important point that will be touched upon again and again, that there is no compelling evidence that efficacy is sacrificed when dose reduction is managed to abate toxicity. More specifically, given the absence of data on dose response curves and the high rates of discontinuation due to toxicity, practitioners should be eager to manage symptoms with supportive care medications and dose reduction. Specifically, when we initiate patients on treatment with abemaciclib, they should be followed closely—initially, weekly or every other week—and dose should be reduced rapidly as indicated to manage symptoms. Similarly empowering patients with education and administering anti-diarrheal therapy to manage toxicity with initial prescribing can go a long way to assist in symptom control. Taking these actions up front could prevent early discontinuation of effective therapy.

Table 1: Summary data of efficacy of frontline CDK4/6 inhibitors in postmenopausal ER-positive breast cancer patients.

Frontline-Metastatic-ER-Positive-Breast-Cancer

ER+, estrogen receptor positive; NS, not significant; NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; PFS, progression-free survival
*Paloma 2 hazard ratio for OS was not statistically significant

Table 2: Summary of adverse events (AE) and serious adverse events (SAE) of frontline CDK4/6 inhibitors in post-menopausal ER-positive breast cancer patients

There are some key differences in how CDK4/6 inhibitors are used in the metastatic setting: activity in combination vs as a single agent, penetration of the blood brain barrier, and evidence for benefit from treatment after progressing on another drug in the same class. For example, abemaciclib is FDA approved as a single agent showing activity with doses at 200mg every 12 hours for patients with metastatic ER-positve/HER2-negative breast cancer1. Abemaciclib has activity in the central nervous system, and is included in the ASCO guidelines among the active agents in ER-positive/HER2-amplified breast cancer with brain metastasis2. Abemaciclib may be an effective therapy after treatment with palbociclib, as a recent cohort of 52 patients previously treated with palbociclib exhibited a clinically meaningful benefit from subsequent therapy with abemaciclib3.

Abemaciclib in Adjuvant High-Risk ER-Positive/HER2-Negative Breast Cancer

Observing the success in patients with metastatic breast cancer, we are seeking to understand if treatment is beneficial in earlier lines of therapy. The MONARCH E trial, evaluating the efficacy and safety of abemaciclib in combination with endocrine blockade in patients with node-positive high-risk ER-positive breast cancer, demonstrated an improvement in disease-free survival. This has been a clinically meaningful addition to our armamentarium of treatment, although careful consideration of management is important as early failure to manage adverse effects can lead to early discontinuation. According to the 4-year follow-up data from MONARCH E, the median invasive disease-free survival benefit previously reported of HR=0.664 (95% CI 0.578-0.762, nominal p<0.0001) was persistent and the absolute difference in invasive disease-free survival was 6.4% (85.8% in the endocrine therapy plus abemaciclib arm versus 79.4% in the endocrine only arm). Overall survival did not meet statistical significance, and the adverse effect profile reflected toxicities known to be associated with abemaciclib, including neutropenia, leukopenia, and diarrhea4. Adjuvant abemaciclib was approved by the FDA in 2021 and is currently approved in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence. Of note, in March 2023, the FDA approval was expanded to remove Ki-67 >20% as a qualifying factor for approval. Patients defined as high risk included those having ≥4 pathologically involved axillary lymph nodes or 1-3 axillary lymph nodes and either tumor grade 3 or tumor size >5cm.

Abemaciclib causes GI toxicity in the form of cramping and diarrhea. Frequently, patients are afflicted with this toxicity, and if they are not optimally managed with anti-diarrheal agents and dose reductions, the patients will prematurely discontinue effective therapy. This is a particular problem in the adjuvant patients: they have often already completed systemic chemotherapy, and their therapeutic enthusiasm wanes as they have completed what they often (incorrectly) perceive as the more important part of therapy. Critical attention to symptom management, patient education, and dose reduction are important, as prescribing at the FDA approved dose will sometimes cause intolerable adverse effects, and early dose reduction will likely lead to reduction of adverse effects and improved compliance with the adjuvant treatment strategy. With all of the CDK4/6 inhibitors there is a large amount of inter-individual variability in exposure, yet in contrast to palbociclib and ribociclib, abemaciclib has three active metabolites that all have clinical activity5. As we don’t have a robust amount of clinical data on dose response to abemaciclib, there has been some hesitation among practitioners to implement strategies to manage toxicity early with dose reduction. Anecdotally, some strategies that have been effective in managing adverse effects include giving a smaller allocation of the drug and seeing the patient 1 and 2 weeks out in follow up, quickly reducing the dose, and sometimes even starting at a lower dose initially. In addition, partnering a new therapy regimen with patient education and loperamide to manage adverse effects can assist in helping patients avoid and manage severe toxicity.

The biggest challenge I have anecdotally observed in clinical practice in patients benefitting from adjuvant abemaciclib is that qualifying patients often don’t have it prescribed for them as part of their adjuvant therapy. Adjuvant abemaciclib was approved in 2021 by the FDA, and while adoption does take time, adoption in clinical practice has been variable.

Clinical Take Aways: When prescribing abemaciclib in patients with metastatic breast cancer, patient education, up-front management of diarrhea, and close follow-up for dose modification and symptom management needs are critical. When prescribing abemaciclib in patients with high-risk ER-positive HER2-negative breast cancer, education, close follow-up, dose modification, and prescribing loperamide to accompany the therapy are also important. Above all, be sure to discuss with high-risk patients the opportunity to reduce their risk with appropriate therapy and the importance of therapy adherence in achieving favorable outcomes.

References
1) Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, O’Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer. Clin Cancer Res. 2017 Sep 1;23(17):5218-5224. doi: 10.1158/1078-0432.CCR-17-0754. Epub 2017 May 22. Erratum in: Clin Cancer Res. 2018 Nov 1;24(21):5485. PMID: 28533223; PMCID: PMC5581697.
2) Giordano SH, Franzoi MAB, Temin S, Anders CK, Chandarlapaty S, Crews JR, Kirshner JJ, Krop IE, Lin NU, Morikawa A, Patt DA, Perlmutter J, Ramakrishna N, Davidson NE. Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2022 Aug 10;40(23):2612-2635. doi: 10.1200/JCO.22.00519. Epub 2022 May 31. PMID: 35640077.
3) Navarro-Yepes J, Kettner NM, Rao X, Bishop CS, Bui TN, Wingate HF, Singareeka Raghavendra A, Wang Y, Wang J, Sahin AA, Meric-Bernstam F, Hunt KK, Damodaran S, Tripathy D, Keyomarsi K. Abemaciclib is effective in palbociclib-resistant hormone receptor-positive metastatic breast cancers. Cancer Res. 2023 Jun 29:CAN-23-0705. doi: 10.1158/0008-5472.CAN-23-0705. Epub ahead of print. PMID: 37384539.
4) Johnston SRD, Toi M, O’Shaughnessy J, Rastogi P, Campone M, Neven P, Huang CS, Huober J, Jaliffe GG, Cicin I, Tolaney SM, Goetz MP, Rugo HS, Senkus E, Testa L, Del Mastro L, Shimizu C, Wei R, Shahir A, Munoz M, San Antonio B, André V, Harbeck N, Martin M; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023 Jan;24(1):77-90. doi: 10.1016/S1470-2045(22)00694-5. Epub 2022 Dec 6. PMID: 36493792.
5) Groenland SL, Martínez-Chávez A, van Dongen MGJ, Beijnen JH, Schinkel AH, Huitema ADR, Steeghs N. Clinical Pharmacokinetics and Pharmacodynamics of the Cyclin-Dependent Kinase 4 and 6 Inhibitors Palbociclib, Ribociclib, and Abemaciclib. Clin Pharmacokinet. 2020 Dec;59(12):1501-1520. doi: 10.1007/s40262-020-00930-x. PMID: 33029704.

EGFR Exon 20 Insertion Mutations – These Are NOT Your Common EGFR Mutations

RR


 

 


Written By: David M. Waterhouse, MD, MPH & Anita Koshy, MD
This promotional educational activity is brought to you by Janssen Biotech, Inc., and is not certified for continuing medical education.
Dr. Waterhouse is a paid consultant writing on behalf of Janssen Biotech, Inc., and must present this information in compliance with FDA requirements applicable to Janssen Biotech, Inc.

It is estimated that approximately 237,000 people in the US will be diagnosed with lung cancer in 2022. Despite advancements in standard-of-care treatments for lung cancer, this disease remains the leading cause of cancer death in both males and females.1 Nonetheless, the burgeoning number of targeted therapies for some types of lung cancer, particularly non-small cell lung cancer (NSCLC), have allowed for improvements in mortality and survival.2 As of 2022, there are ~20 targeted therapies for ~9 actionable driver mutations in stage IV NSCLC.3,4 In order to determine optimal targeted therapies, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend comprehensive biomarker testing, like next-generation sequencing (NGS), for all eligible patients at diagnosis of advanced NSCLC.5

Common EGFR Mutations (Exon 19 deletion and Exon 21 [L858R] mutations)

Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in NSCLC, and EGFR driver mutations may be found in as many as 28% of metastatic NSCLC patients.6 Tyrosine kinase inhibitors (TKIs) directed against EGFR were among the first molecular targeted agents used for treatment of advanced NSCLC.7 Initial studies of EGFR TKIs showed that patient characteristics associated with EGFR mutations, such as non-smoking status, female gender, East Asian origin, and adenocarcinoma histology suggested a greater benefit from EGFR TKIs compared with first-line chemotherapy.8 Later studies identified gene mutations that could target the kinase domain of EGFR and predicted response to such inhibitors. The variable deletions of at least 3 amino acid residues in exon 19, as well as the single point mutation leucine-858 to arginine (L858R) in exon 21, are often referred to as “common” activating EGFR mutations and represent the vast majority (90%) of all observed EGFR kinase domain mutations in NSCLC.8 (Figure 1)EGFR-Mutations

EGFR Exon 20 Insertion Mutations

Exon 20 insertion mutations are the third most prevalent type of activating EGFR mutations in NSCLC and are associated with a poor prognosis.9-11 These mutations are also enriched in women, non-smokers, Asian populations, and those with adenocarcinoma. Exon 20 insertion mutations, however, lack the key structural features that confer sensitivity of L858R and exon19 deletion mutations to first-and second-generation EGFR inhibitors. In-frame base pair insertions in exon 20 result in activation of EGFR, but, unlike the common activating EGFR mutations, they are associated with reduced affinity to most clinically available EGFR TKIs indicated for common EGFR mutations. Data are limited and variable, but multiple studies found that patients with EGFR exon 20 insertion mutations had an overall response rate of 0% to 8.7% when treated with first-, second-, or third-generation EGFR TKIs.12-16 (Figure 2)

Median-PFS-First-Second-Generation_TKI

*These data were taken from a retrospective observational study.16
†Common mutations include L858R, L861Q, and exon 19 deletions.16
‡These data were taken from multiple sources: a cohort study, a prospective post hoc analysis of phase 2 and phase 3 trials, a single-center retrospective analysis, and a systematic literature review and meta-analysis.12-14
HR, hazard ratio; ORR, overall response rate; PFS, progression-free survival.

Study results also demonstrate limited efficacy of immuno-oncology (IO) monotherapy in this patient population compared to patients with wild-type EGFR. In a retrospective study using real-world data, patients with EGFR exon 20 insertion mutation-positive NSCLC were associated with a 58% increased risk of shorter time to next-line therapy after first-line IO monotherapy compared to patients with wild-type NSCLC.17

The NCCN Guidelines® do not recommend most TKIs or IO monotherapy for treating patients with mNSCLC and EGFR exon 20 insertion mutations in the first- or second-line setting. Instead, the Guidelines recommend platinum-based chemotherapy as the standard first-line treatment for NSCLC with EGFR exon 20 insertion mutations.5§

§Exceptions include p.A763_Y764insFQEA and p.A763_Y764insLQEA.5

EGFR Testing

The NCCN Guidelines recommend comprehensive biomarker testing, like NGS, prior to the initiation of first-line therapy, if clinically feasible.5 Despite that recommendation, rates of broad biomarker testing remain low, according to real-world evidence.18,19 In a retrospective observational chart review study among 3,474 patients with advanced NSCLC receiving first-line therapy in the US Oncology Network, the EGFR testing rate was found to be 70%, but comprehensive NGS testing was completed in only 42% of patients.20 Failure to order comprehensive NGS testing is particularly problematic when it comes to identifying EGFR exon 20 insertions. There are over 100 unique EGFR exon 20 insertion variants, and polymerase chain reaction (PCR) testing can miss approximately 50% of the insertions identified by NGS.21 (Figure 3)

EGFR-Mutations-Foundation-Medicine

||Analysis from mutation profiles of 36,465 lung adenocarcinomas from Foundation Medicine (Cambridge, MA) FoundationInsights database, which is a database of 315,688 patient genomic profiles across 150 cancer types.
¶Commercially available qPCR methods were Roche cobas® EGFR mutation test v2 and Qiagen therascreen EGFR RGQ PCR kit.

Another notable issue is the accurate application of NGS data to clinical care. In multiple retrospective, observational cohort studies, approximately 17% to 24% of treatment-naive and 14% to 22% of second-line patients with EGFR exon 20 insertions received EGFR TKIs.11,17,22** Studies also found that approximately 7% to 40% of treatment-naive and 26% to 41% of second-line patients received IO monotherapy.17,22,23 These therapies (ie, most TKIs indicated for common mutations†† and IO monotherapies) are not recommended for first- or second-line therapy for EGFR exon 20 insertion mutations.5

**EGFR TKIs included first-, second- and third-generations.
††Exceptions include p.A763_Y764insFQEA and p.A763_Y764insLQEA.

Current Treatment Strategies for Patients With Exon 20 Insertion Mutations
Chemotherapy with a platinum doublet remains the recommended treatment option for the first-line treatment of patients with an EGFR exon 20 insertion mutation.5 When many of these patients progress, subsequent treatment options are needed. The NCCN Guidelines recommend amivantamab-vmjw or mobocertinib as subsequent therapy options for patients with EGFR exon 20 insertion mutations who have progressed on or after initial systemic therapy.5

Conclusion:

  • Advances made in the treatment of NSCLC have improved patient mortality and survival,2 and these advancements are due in part to the discovery of actionable mutations, like common EGFR mutations, and targeted therapies3,4,7,8
  • Multiple studies have found, however, that patients with EGFR exon 20 insertion mutations had a poor overall response when treated with first-, second-, or third-generation EGFR TKIs,11-15,17 and that IO monotherapies provide little benefit as a first-line treatment in patients with EGFR mutations, including exon 20 insertions17
  • The NCCN Guidelines recommend:
    • Testing eligible patients with mNSCLC for targetable genetic alterations to both identify potentially appropriate targeted therapies and avoid therapies unlikely to provide clinical benefit5
    • Treating patients who harbor a common EGFR mutation (exon 19 deletion and exon 21 [L858R] mutations) with an EGFR TKI in the first line of treatment, whereas those with an EGFR exon 20 insertion mutation are best treated with a regimen containing a platinum doublet5
    • Amivantamab-vmjw or mobocertinib as subsequent therapy options for patients with EGFR+ mNSCLC with exon 20 insertion mutations who have progressed on or after initial systemic therapy per the NCCN Guidelines5

References
1. National Cancer Institute. Cancer stat facts: common cancer sites. Accessed September 30, 2022. https://seer.cancer.gov/statfacts/html/common.html
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021.CA Cancer J Clin. 2021;71:7-33.
3. Benjamin DJ, Haslam A, Gill J, Prasad V. Targeted therapy in lung cancer: Are we closing the gap in years of life lost? Cancer Med. 2022;11(18):3417-3424.
4. Targeted Therapy in Metastatic Non–Small Cell Lung Cancer: Recent Updates and Controversies. Angel Qin. ASCO Daily News. Published January 19, 2022. Accessed November 14, 2022. https://dailynews.ascopubs.org/do/10.1200/ADN.22.200810/
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.6.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed December 2, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in anyway.
6. Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7(6):596-609.
7. Luo SY, Lam DC. Oncogenic driver mutations in lung cancer. Transl Respir Med. 2013;1(1):6.
8. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28 (Suppl 1):S24-S31.
9. Arcila ME, Nafa K, Chaft JE, et al. EGFR exon20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013;12(2):220-229.
10. Leal JL, Alexander M, Itchins M, et al. EGFR exon 20 insertion mutations: clinicopathological characteristics and treatment outcomes in advanced non-small cell lung cancer. Clin Lung Cancer. 2021;22(6):e859-e869.
11. Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer. 2021;162:154-161.
12. Wu JY, Yu CJ, Shih JY. Effectiveness of treatments for advanced non-small-cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations. Clin Lung Cancer. 2019;20:e620-e630.
13. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.Lancet Oncol. 2015;16(7):830-838.
14. Kate S, Chougule A, JoshiA, et al. Outcome of uncommon EGFR mutation positive newly diagnosed advanced non-small cell lung cancer patients: a single center retrospective analysis. Lung Cancer (Auckl). 2019;10:1-10.
15. Kwon CS, Lin HM, Crossland V, et al. Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes. Curr Med Res Opin. 2022;38(8):1341-1350.
16. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018;24:638-646.
17. Girard N, Minchom A, Ou SI, et al. Comparative clinical outcomes between EGFR ex20 ins and wild type NSCLC treated with immune checkpoint inhibitors. Clin Lung Cancer. 2022;23(7):571-577.
18. Paz-Ares L, Gondos A, Saldana D, et al. Genomic testing among patients with newly diagnosed advanced non-small cell lung cancer in the United States: A contemporary clinical practice patterns study. Lung Cancer. 2022;167:41-48.
19. Waterhouse DM, Tseng WY, Espirito JL, Robert NJ. Understanding contemporary molecular biomarker testing rates and trends for metastatic NSCLC among community oncologists. Clin Lung Cancer. 2021;22(6):e901-e910.
20. Robert N, Chen L, Espirito J, et al. Trends in molecular testing for metastatic non-small cell lung cancer in the US Oncology Network community practices. J Thorac Oncol. 2021;16(10) (suppl):S1169.
21. Bauml J, Viteri S, Minchom A, et al. Underdiagnosis of EGFR exon 20 insertion mutation variants: estimates from NGS-based real-world datasets. Presented at: the IASLC 2020 World Conference on Lung Cancer; January 28-31, 2021;Singapore.
22. He J, Pericone CD, Vanderpoel J. Real-world patient characteristics, treatment patterns, and mutation testing patterns among US patients with advanced non-small cell lung cancer harboring EGFR mutations. Adv Ther. 2022;39(7):3347-3360.
23. Choudhury NJ, Schoenfeld AJ, Flynn J, et al. Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR exon 20 insertions. Clin Cancer Res. 2021;27(10):2920-2927.

© Janssen Biotech, Inc. 2022 12/22 cp-345345v1

XPOVIO® (selinexor): A Treatment Approved for Multiple Myeloma as Early as First Relapse

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Author: Cristina Gasparetto, MD
Sponsored by: Karyopharm Therapeutics, Inc.
Dr. Gasparetto is a paid consultant for Karyopharm Therapeutics, Inc. and has been compensated.

Multiple myeloma (MM) remains an incurable hematologic cancer due to the clonal nature of the disease.1 With each relapse, cancer cells undergo clonal evolution and acquire new mutations that render them resistant to certain treatments.1 Triplet therapies combining proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (CD38-mAbs) have improved patient outcomes and their use has steadily increased over the past decade.2,3 When patients relapse after exposure to daratumumab (a CD38-mAb), the prognosis becomes unfavorable; even if patients previously responded to PIs or IMiDs, median survival may not reach one year.3 A significant unmet need therefore remains for providing durable disease control for patients with MM.1

For patients with previously-treated MM, the National Comprehensive Cancer Network® (NCCN®) recommends a new triplet regimen should preferably include drugs or drug classes patients have not been exposed to, or not exposed to for at least 6 months.4 For patients with MM who are triple class exposed, a selective inhibitor of nuclear export (SINE) may be a potential treatment class to consider in early relapsed (1-3 prior therapies) MM.4 Once-weekly XPOVIO® (selinexor), is a first-in-class, oral SINE compound approved as early as first relapse in MM that reversibly inhibits exportin 1 (XPO1).5 This action leads to accumulation of tumor suppressor proteins in the nucleus and reductions in several oncoproteins, such as c-myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells.5 Oral, once weekly selinexor (XPOVIO®) in combination with bortezomib and dexamethasone (XVd) is recommended by the NCCN as a Category 1 therapeutic option in early relapsed (1 to 3 prior therapies) MM.4

The efficacy and safety of XPOVIO was assessed in a phase 3, randomized, open-label trial comparing XPOVIO (100 mg once weekly) in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) with Vd alone in patients exposed to one to three prior lines of therapy.6 Patient disease characteristics were well balanced in both treatment groups and the primary endpoint was progression-free survival (PFS).5,6 Patients in the XVd group demonstrated a median PFS of 13.9 months (95% CI: 11.73-NE) compared with 9.5 months (95% CI: 8.11-10.78) in the Vd group (HR 0.70 [95% CI: 0.53-0.93], P=0.0075).6 In patients treated with XVd, a greater median PFS was consistently observed in certain subgroups compared with patients treated with Vd (Figure 1).6,7 When comparing patients 65 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and a higher incidence of serious adverse reactions (56% vs 47%).5

XPOVIO-Combination-Demonstrated-Sustained-PFSFigure 1. Median PFS in the XVd and Vd treatment groups (primary endpoint) and in select patient subgroups in the XVd trial.

Oral, once-weekly XPOVIO dosage may be adjusted to help mitigate potential adverse reactions (ARs).5 The indicated starting dose of XPOVIO is 100 mg once weekly and the dose may be reduced to 80 mg, 60 mg, or 40 mg based on ARs.5 Dose reductions were permitted in the XVd trial to help mitigate ARs – 65% of patients in the XVd group had a dose reduction and the median dose of XPOVIO in that group was 80 mg once weekly.5,7 Patients in my clinical practice typically get reduced from 100 mg to 60 mg once weekly and experience minimal tolerability issues at 60 mg. In an exploratory post-hoc analysis of the XVd trial, efficacy was maintained with XPOVIO dose reductions (Figure 2).7

Efficacy-Maintained-Even-With-XPOVIO-Dose-ReductionFigure 2. Median PFS in XPOVIO dose-reduced patients in the XVd trial.

XVd was not associated with serious organ toxicities of the cardiac, pulmonary, renal, or hepatic systems.6,7 Warnings and precautions include life-threatening thrombocytopenia and neutropenia, gastrointestinal toxicities, severe life-threatening hyponatremia, serious infection, and life-threatening neurological toxicities.5 The most common adverse reactions (≥20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting (Figure 3).5 The XVd trial protocol required a prophylactic 5-HT3 antagonist to address nausea but allowed for other interventions as required.7 Nausea events were reported in 50% of patients, however, treatment-related nausea associated with XPOVIO diminished over time; 92% of nausea cases were resolved/resolving in the first month of treatment.7 Patients should be counseled on what to expect with XPOVIO therapy and monitored throughout treatment, with more frequent monitoring during the first three months of treatment.5

Figure 3. Adverse reactions reported in the XVd trial.

Below we consider 2 hypothetical patients where XPOVIO may be considered.

Patient A is a 66-year-old woman with relapsed/refractory MM. She was started on lenalidomide, bortezomib, and dexamethasone, and received autologous stem cell transplant (ASCT) followed by lenalidomide maintenance, which she did well on for 16 months. Upon relapsing, she was given daratumumab, pomalidomide with dexamethasone, and after 7 months, imaging confirmed that her MM progressed again. Given her DPd exposure, Patient A (RVd → ASCT → R → DPd) may be a candidate for a class switch to XVd.

Patient B is a 74-year-old man with a history of hypertension and was diagnosed with MM 2 years ago. Because of his hypertension, he was unable to start a PI due to risk of cardiotoxicity and he is ASCT ineligible. His healthcare provider started him on daratumumab, lenalidomide, and dexamethasone (DRd), but after 2 years, he has relapsed. A class switch to XPOVIO could be considered for Patient B as his second-line therapy.

Healthcare providers should consider patients’ individual clinical characteristics when making treatment decisions. Consider switching class with XPOVIO® (selinexor) for patients at relapse, including those who have been exposed to a CD38-mAb–based regimen.5 Based on the results of the XVd trial and considering the clonal nature of MM, switching patients to XPOVIO may be an option to consider.

INDICATIONS
XPOVIO® (selinexor) is a prescription medicine approved:
• in combination with bortezomib and dexamethasone to treat adult patients with multiple myeloma who have received at least one prior therapy.
• in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti‐CD38 monoclonal antibody.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia: XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma.
Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of bleeding. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection.
Monitor more frequently during the first 3 months of treatment. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients.

Nausea/Vomiting/Diarrhea: Provide prophylactic antiemetics or treatment as needed.

Anorexia/Weight Loss: Monitor weight, nutritional status, and volume status at baseline and throughout treatment and provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Hyponatremia: XPOVIO can cause severe or life-threatening hyponatremia.
Monitor sodium level at baseline and throughout treatment.

Serious Infection: XPOVIO can cause serious and fatal infections. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

Neurological Toxicity: XPOVIO can cause life-threatening neurological toxicities.
Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.
Advise patients to refrain from driving and engaging in hazardous occupations or activities until the neurological toxicity fully resolves. Institute fall precautions as appropriate.

Embryo-Fetal Toxicity: XPOVIO can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

Cataracts: New onset or exacerbation of cataract has occurred during treatment with XPOVIO. The incidence of new onset or worsening cataract requiring clinical intervention was reported.

ADVERSE REACTIONS

The most common adverse reactions (ARs) (≥20%) in patients with multiple myeloma who received XVd were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting.

Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia.

Fatal ARs occurred in 6% of patients within 30 days of last treatment. Serious ARs occurred in 52% of patients. Treatment discontinuation rate due to ARs was 19%. The most frequent ARs requiring permanent discontinuation in >2% of patients included fatigue, nausea, thrombocytopenia, decreased appetite, peripheral neuropathy and vomiting. Adverse reactions led to XPOVIO dose interruption in 83% of patients and dose reduction in 64% of patients.

USE IN SPECIFIC POPULATIONS

No overall difference in effectiveness of XPOVIO was observed in patients >65 years old when compared with younger patients. Patients ≥65 years old had a higher incidence of discontinuation due to an adverse reaction (AR) and a higher incidence of serious ARs than younger patients.

The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.

Please see full Prescribing Information.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

© 2022 Karyopharm Therapeutics Inc. US-XPOV-10/22-00003

References
1. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021;18(2):71-84. doi:10.1038/s41571-020-0427-6
2. Braunlin M, Belani R, Buchanan J, Wheeling T, Kim C. Trends in the multiple myeloma treatment landscape and survival: a U.S. analysis using 2011-2019 oncology clinic electronic health record data. Leuk Lymphoma. 2021;62(2):377-386. doi:10.1080/10428194.2020.1827253
3. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.5.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed October 18, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
5. XPOVIO (selinexor) [prescribing information]. Karyopharm Therapeutics Inc. https://www.karyopharm.com/wp-content/uploads/2019/07/NDA-212306-SN-0071-Prescribing-Information-01July2019.pdf
6. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. The Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3
7. Data on File. Karyopharm Therapeutics Inc. 2021. Published online 2021.

OPDIVO® (nivolumab) for the Adjuvant Treatment of High-Risk Urothelial Carcinoma*

RR

*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.
Written by: Terence Friedlander, MD
Professor of Medicine, Division of Hematology/Oncology, Zuckerberg San Francisco General Hospital, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

Content sponsored by: Bristol Myers Squibb
Dr Friedlander is a paid consultant for BMS and was compensated for his contribution in drafting this content.

Overview of High-Risk Urothelial Carcinoma*
Currently, radical resection with or without perioperative therapy is the standard of care for treating high-risk urothelial carcinoma (UC).1* However, there is still a high chance of recurrence within 2 years of radical resection, with less favorable survival rates for the high-risk patient population.1 While neoadjuvant therapy has an established role in treating high-risk UC,* data are less clear regarding the role of adjuvant therapy.2 In a retrospective observational cohort study of patients 65 years or older with UC at high risk of recurrence after radical resection, including patients who received neoadjuvant chemotherapy, median disease-free survival (mDFS) was determined to be 13.5 months.1 Cisplatin-based chemotherapy is the neoadjuvant standard of care, but prior to 2021 there were no FDA-approved adjuvant therapy options.1-3 Studies have shown that adjuvant chemotherapy may delay recurrence and improve overall survival (OS), but these studies have not definitively shown a survival benefit, largely due to inadequate sample sizes.2 Additionally, approximately 50% of patients are ineligible for cisplatin-based treatment.1 As a result, there is a high unmet need for this difficult-to-treat population, and it is important for the urologist, oncologist, and patient to discuss and align on perioperative treatments at the time of diagnosis and early in the patient journey.1,2,4 Entering the adjuvant treatment landscape, immune checkpoint inhibitors may be an additional treatment option for HCPs to consider for their patients with high-risk UC.1,2*

Adjuvant OPDIVO in High-Risk Urothelial Carcinoma*
OPDIVO is approved and indicated for the adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5 The approval is based on Checkmate 274, a phase 3, multicenter, double-blind, randomized trial of adjuvant OPDIVO versus placebo.6 More information on the study design can be found in the images below. Baseline characteristics were balanced across treatment arms.6
Checkmate 274Important Safety Information
Select Important Safety Information
In Checkmate 274, serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). The most-common adverse reactions reported in ≥20% of patients were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and UTI. OPDIVO was discontinued or delayed due to adverse reactions in 18% and 33% of patients, respectively.5

OPDIVO is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

OPDIVO may cause severe infusion-related reactions. In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.5 For additional information regarding infusion-related reactions, please see Important Safety Information for OPDIVO.
Checkmate-274-Defined-High-Risk-PatientsDouble-median-DFS-with-OPDIVOCheckmate 274 was not powered to detect differences in the treatment effect at extended follow-up analysis; therefore, results from this exploratory analysis should be interpreted with caution.

Adjuvant OPDIVO demonstrated superior disease-free survival (DFS) compared with placebo at the primary analysis (minimum follow-up of 5.9 months).5,6 Median DFS was 20.8 months with OPDIVO versus 10.8 months with placebo (HR=0.70 [95% CI: 0.57–0.86];P=0.0008).5 OS was also evaluated as a secondary endpoint, but at the time of the planned interim analysis, these data were immature with 33% of deaths in the ITT population; in the UTUC subpopulation, 37 deaths occurred, 20 of which occurred with OPDIVO versus 17 with placebo.5 Although the subgroup analyses were not statistically powered, for patients with prior neoadjuvant cisplatin therapy (n=308), the DFS hazard ratio was 0.52 [95% CI: 0.38–0.71] and for patients without prior neoadjuvant cisplatin therapy (n=401), the DFS hazard ratio was 0.92 [95% CI: 0.69–1.21].6 In additional exploratory subgroup analyses, no improvement in DFS was observed with nivolumab compared to placebo in patients with UTUC (n=149) the unstratified DFS hazard ratio was 1.15 (95% CI: 0.74–1.80); in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio was 0.83 (95% CI: 0.64–1.08).5

At the extended follow-up analysis (minimum follow-up of 11.0 months), mDFS was doubled with adjuvant OPDIVO compared with placebo. Median DFS was 22.0 months with OPDIVO versus 10.9 months with placebo (HR=0.70 [95% CI: 0.57–0.85]).12

Summary/conclusions
Given the high unmet need in this difficult-to-treat population, the call for approved adjuvant treatment options continues to rise.1,2 Adjuvant OPDIVO offers a chance to change the future for patients with high-risk UC as the only FDA-approved adjuvant option for adult patients with UC at high risk of recurrence after radical resection regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5,6,12 In Checkmate 274, OPDIVO significantly extended mDFS at the time of primary analysis and doubled mDFS at the time of extended follow-up analysis.5,6,12 Further data will be generated for the secondary endpoint of OS, which may provide greater insight into the efficacy of OPDIVO in this context.6,8 Given the clinical profile of Checkmate 274 and subsequent FDA approval, OPDIVO may help extend DFS for appropriate patients in need of treatment in the adjuvant UC setting.5,6,12

*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.

Additional Definitions
CI=confidence interval; HCP=healthcare provider; HR=hazard ratio; ITT=intent to treat; PD-L1=programmed death ligand 1; UTUC=upper tract urothelial carcinoma.

Indication
OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

Important Safety Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies
OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune- mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD-1/PD- L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60- minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation
There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions
In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%).

Common Adverse Reactions
In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

Please see US Full Prescribing Information for OPDIVO.

References
1. Drakaki A, Pantuck A, Mhatre SK, et al. “Real-world” outcomes and prognostic indicators among patients with high-risk muscle-invasive urothelial carcinoma. Urol Oncol. 2021;39:76.e15-76.e22.
2. Referenced without permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed August 4, 2022. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
3. Apolo AB, Msaouel P, Niglio S, et al. Evolving Role of Adjuvant Systemic Therapy for Kidney and Urothelial Cancers. Am Soc Clin Oncol Educ Book. 2022;42:1-16. doi:10.1200/EDBK_350829.
4. Nayan M, Bhindi B, Yu JL, et al. The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: A time-series analysis. Can Urol Assoc J. 2016;10(1-2):25-30.
5. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
6. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114.
7. Bajorin DF, Witjes JA, Gschwend JE, et al. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab versus placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at ASCO GU 2021. Abstract 391.
8. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114 [supplementary appendix].
9. American Cancer Society. Bladder cancer early detection, diagnosis, and staging. Accessed August 5, 2022. https://www.cancer.org/content/dam/CRC/PDF/Public/8559.00.pdf.
10. Data on file. NIVO 639. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
11. Witjes JA, Bajorin DF, Galsky MD, et al. Results for patients with muscle-invasive bladder cancer in the CheckMate 274 trial. Poster presentation at ASCO 2022. Abstract 4585.
12. Galsky MD, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the phase 3 CheckMate 274 trial of adjuvant nivolumab in patients who underwent surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at the American Urological Association (AUA) Annual Meeting 2022. Abstract 22-3807.

© 2022 Bristol-Myers Squibb Company. OPDIVO® and the related logos are trademarks of Bristol-Myers Squibb Company. 1506-US-2200368 8/22

Opdualag™ (nivolumab and relatlimab-rmbw): A New Dual I-O Option in the 1L Treatment of Metastatic Melanoma

RR

Written By: Leonel Fernando Hernandez Aya, MD. Division of Medical Oncology, Department of Medicine, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center

Content Sponsored by: Bristol Myers Squibb
Dr Hernandez Aya is a paid consultant for BMS and was compensated for his contribution in drafting this content.

See additional definitions of abbreviations used throughout the article at the bottom of this page.

Overview of Metastatic Melanoma
Since the approval of anti–CTLA-4 in 2011 for metastatic melanoma, immuno-oncology(I-O) has transformed treatment outcomes.1 There are now several approved I-O options, and of those approved for the treatment of metastatic melanoma, dual immunotherapy in particular has had long-term success.2 The first dual immunotherapy, approved in 2015, consisted of PD-1 and CTLA-4 checkpoint inhibitors for the 1L treatment of unresectable or metastatic melanoma, regardless of BRAF mutation status.1,3,4 This anti–PD-1 and anti–CTLA-4 combination showed benefit in overall survival (OS) compared with anti–CTLA-4 alone.5 In general, the safety profile was consistent with previous experience with anti–PD-1 or anti–CTLA-4 alone.4 Until March 2022, this dual anti–PD-1 and anti–CTLA-4 immunotherapy was the only option indicated for the 1L treatment of unresectable or metastatic melanoma.3,6 Opdualag, the second approved dual immunotherapy, has provided an additional treatment option for nivolumab-monotherapy–appropriate patients with unresectable or metastatic melanoma.6-8

Opdualag
Opdualag is a dual immunotherapy option combining an anti–PD-1, nivolumab, with the first-in-class anti–LAG-3, relatlimab, in a fixed-dose formulation.7,8 PD-1 and LAG-3 are two distinct inhibitory immune checkpoints.7 Combined PD-1 and LAG-3 inhibition results in increased T-cell activation compared to the activity of either antibody alone. This initiates an improved anti-tumor immune response.8

Opdualag is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.8 The approval is based on RELATIVITY-047, a phase 3, randomized, double-blind, global study of Opdualag versus nivolumab monotherapy.7 Patients were stratified by AJCC v8 M stage, BRAF, PD-L1, and LAG-3 status.7 Key exclusion criteria include patients with active or untreated brain or leptomeningeal metastases, uveal melanoma, active autoimmune disease, or medical conditions requiring systemic treatment with moderate- or high-dose corticosteroids or immunosuppressive medications.8

RELATIVITY-047 enrolled 714 patients who were randomized 1:1 to receive Opdualag (480 mg nivolumab/160 mg relatlimab as a fixed-dose combination[FDC]) every 4 weeks (n=355) or nivolumab 480 mg every 4 weeks (n=359).8 The primary endpoint was progression-free survival(PFS), and secondary endpoints were OS and overall response rate(ORR). PFS was determined by BICR using RECIST v1.1. Baseline characteristics were balanced across both treatment arms.7

Study design8

Median duration of treatment for Opdualag at the 19.3-month median follow-up was 8.3 months.7,9 Treat until disease progression or unacceptable toxicity.8

*Patients were allowed to have received prior adjuvant and neoadjuvant melanoma therapy. Anti–PD-1, anti–CTLA-4, or BRAF-MEK therapy was allowed as long as there was at least 6 months between the last dose of therapy and date of recurrence; interferon therapy was allowed as long as the last dose was at least 6 weeks prior to randomization.8† PD-L1 expression (≥1% vs <1%) using PD-L1 IHC 28-8 pharmDx test.8‡ LAG-3 expression (≥1% vs <1%) using a clinical trial assay.8§ The final analysis of OS was not statistically significant.8

Opdualag is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions (IMARs) including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); and embryo-fetal toxicity.

Opdualag demonstrated superior PFS compared to nivolumab at the primary analysis(median of 13.2 months) with curve separation as early as 3 months and sustained over time.7,8 Median PFS (mPFS)was 10.1 months with Opdualag versus 4.6 months with nivolumab (HR=0.75; 95% CI: 0.62–0.92; P=0.0055).8 Similarly, patients who received Opdualag had longer PFS regardless of key prognostic indicators, such as the AJCC metastasis stage of the tumor, LDH level, and tumor burden.7

At the follow-up analysis (median of 19.3 months), mPFS was 10.22 months with Opdualag and 4.63 months with nivolumab (HR=0.78; 95% CI: 0.64-0.94).10 OS and ORR were also evaluated.8 The final analysis for the secondary endpoint of OS was not statistically significant (threshold for significance was P<0.04302), and median OS (mOS)was not reached with Opdualag compared with nivolumab, which resulted in a mOS of 34.1 months (HR=0.80; 95% CI: 0.64–1.01; P=0.0593). Additionally, the ORR was higher with Opdualag (43%) versus nivolumab (33%), with the median DOR not yet reached for both treatment arms.8,10 ORR was not formally tested based on the testing hierarchy.8

Progression-free survival at the 19.3-month median follow-up10*†‡

Symbols represent censored observations.
*Assessed by BICR.8† Final PFS analysis.8‡ Kaplan-Meier estimate.8§ Based on stratified Cox proportional hazard model.8II Based on stratified log-rank test.8

Overall survival10*

*At the time of the final OS analysis, which was event-driven and occurred after the final PFS analysis.8† Based on stratified Cox proportional hazard model.8‡ Based on stratified log-rank test.8§ Not significant at alpha level 0.04302.8

In RELATIVITY-047, Opdualag had no additional safety events and similar most common Grade 3/4 AEs versus nivolumab monotherapy.7,8 Adverse reactions occurring in ≥15% of patients receiving Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), diarrhea (24%), nausea (17%), headache (18%), hypothyroidism (17%), decreased appetite (15%), and cough (15%).8

Toxicity was graded per NCI CTCAE v5.
*Clinically relevant adverse reactions in <15% of patients who received Opdualag included vitiligo, adrenal insufficiency, myocarditis, and hepatitis.8† Includes multiple terms.8

Opdualag is a FDC administered as a 30-minute intravenous infusion every 4 weeks.8 A FDC is the co-formulation of 2 active ingredients in a single vial administered as a single infusion, which may help reduce preparation and infusion times and could help minimize potential risk of administration errors.7,8,11 Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.8

Summary/conclusions
Dual immunotherapy has changed the metastatic melanoma treatment landscape.2 Currently there are 2 dual immunotherapy options available for 1L treatment of adult patients with unresectable or metastatic melanoma.3,8 As the newest dual immunotherapy, Opdualag more than doubled mPFS with a similar safety profile compared with nivolumab.8 Opdualag can be used for the treatment of all nivolumab monotherapy-appropriate patients, providing the opportunity for more patients with unresectable or metastatic melanoma to receive a dual immunotherapy.8 From my clinical experience, “it is great to have another treatment option for patients with metastatic melanoma.”

Indication for Opdualag
Opdualag is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Important Safety Information for Opdualag
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions (IMARs) listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose IMARs are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis
Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis
Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies
Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction
Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-Mediated Dermatologic Adverse Reactions
Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis
Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions
The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received Opdualag or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: Cardiac/Vascular: pericarditis, vasculitis; Nervous System: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica; Endocrine: hypoparathyroidism; Other (Hematologic/Immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions
Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdualag for at least 5 months after the last dose of Opdualag.

Lactation
There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions
In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in ≥1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities
The most common adverse reactions reported in ≥20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in ≥20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see US Full Prescribing Information for Opdualag.

Indication for OPDIVO® (nivolumab) + YERVOY® (ipilimumab)
OPDIVO, in combination with YERVOY, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

Important Safety Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%).

Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%).

Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%).

Immune-Mediated Endocrinopathies
OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%).

Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation
There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions
In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).

Common Adverse Reactions
In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

References
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© 2022 Bristol-Myers Squibb Company. OPDIVO®, YERVOY®, Opdualag™, and the related logos are trademarks of Bristol-Myers Squibb Company.
7356-US-2200441 8/22

Additional Definitions
AJCC=American Joint Committee on Cancer; BICR=blinded independent central review; CI=confidence interval;CTLA-4=cytotoxic T-lymphocyte antigen 4; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; HR=hazard ratio;IHC=immunohistochemistry; IV=intravenous;LAG-3=lymphocyte-activation gene 3; LDH=lactate dehydrogenase; M stage=metastasis stage; mo=month; no=number; NS=not significant; PD-1=programmed death receptor-1; PD-L1=programmed death ligand 1; q4w=every 4 weeks; RECIST=Response Evaluation Criteria In Solid Tumors.